C. George Rochester, Ph.D. FDA Anti-Infective Advisory Committee Meeting

1. Large Comparative Safety Trialin an Usual Care Setting________________________________________________________________________________________________ C. George Rochester, Ph.D. FDA Anti-Infective Advisory Committee Meeting Mathematical Statistician, Division of Biometrics III January 8, 2003 RochesterG@cder.fda.gov

2. Study 3014:Elements of Study Design (1)_______________________________________________________________________________________________ • Randomized, comparative, open-label • Community-acquired respiratory tract infections: CAP, AECB, or AS • Approximately 12,000 subjects per arm • Telithromycin (TEL) 800 mg qd orally x 5 days for AS; 7-10 days for CAP or AECB • Comparator: Amoxicillin-clavulanic acid (AMC) 875 mg/125 mg bid x 7-10 days for all indications FDA Anti-Infective AC Meeting

3. Elements of Study Design (2)_______________________________________________________________________________________________ • Usual care setting with relaxed inclusion and exclusion criteria and included subjects with CARTIs • Indication distribution: 10% CAP, 30% AECB, 60% AS • Target: -  40% subjects with CAP/AECB, -  35% subjects  50 years of age • Subjects with cardiovascular disease, renal or hepatic impairment, and concomitant drug use, such as, subjects taking that inhibit or are metabolized by CYP3A4 or CYP2D6 FDA Anti-Infective AC Meeting

4. Definition of Adverse Events of Special Interest (AESIs) _________________________________________________________________________ FDA Anti-Infective AC Meeting

5. Overall Adverse Event Rates_______________________________________________________________________________________________ • Phase 3 trials:  50% of subjects had AEs • Study 3014: had many subjects with co-morbidities - diabetes, renal or hepatic impairment, cardiovascular disease, many concomitant drugs  23% of subjects had AEs • Subjects with CAP accounted for 10% of study population • Usual care setting - population may be more heterogenous than those enrolled in previous phase 3 trials FDA Anti-Infective AC Meeting

6. Adverse Events: Subgroups____________________________ FDA Anti-Infective AC Meeting

7. Hepatic AESI: Investigation Process_______________________________________________________________________________________________ • Hepatic laboratory testing was done at Pretherapy (Day 1) and Post-therapy (Day 17-22) clinic visits • Alteration in hepatic laboratory values of increase in ALT > 3xULN was used to flag potential hepatic AESIs • Follow-up to return to baseline or “sufficient decline” was done for subjects with potential hepatic AESI - 6 months • Management algorithms were not utilized: could have guided investigators with minimum expectation for follow-up of AEs and minimize missing critical data and improve completeness of case documentation • Adjudication by blinded CECs was planned at regular intervals but was largely done in batch at the end of the trial FDA Anti-Infective AC Meeting

8. Hepatic AESI Resolution____________________________ FDA Anti-Infective AC Meeting

9. Changes in ALT: Normal Baseline____________________________ FDA Anti-Infective AC Meeting

10. Changes in AST: Normal Baseline____________________________ FDA Anti-Infective AC Meeting

11. Changes in Hepatic Analytes at any Post-Therapy Time Point____________________________________________________________________________________ FDA Anti-Infective AC Meeting

12. Combined ALT and Bilirubin Changes at any Post-Therapy Time Point____________________________________________________________________________________ FDA Anti-Infective AC Meeting

13. Changes in ALT among Telithromycin-treated Subjects: By Duration____________________________ FDA Anti-Infective AC Meeting

14. Subjects who Met Hepatic Endpoint Definition_______________________________________________________________________________________________ • Subjects who met the definition of a possibly drug related hepatic event: • TEL: 3/12,096 (95% C.I., 0.5 - 7.2/10,000) • AMC: 2/11,883 (95% C.I., 0.2 - 6.1/10,000) FDA Anti-Infective AC Meeting

15. Case # 0187-026___________________________________________________________________________________________________________________________________________________________________________________ FDA Anti-Infective AC Meeting

16. Case # 3440-001___________________________________________________________________________________________________________________________________________________________________________________ FDA Anti-Infective AC Meeting

17. Case 2004-002___________________________________________________________________________________________________________________________________________________________________________________ FDA Anti-Infective AC Meeting

18. Summary ________________________________________________________________________________________________________________________________________________ • Hepatic AESIs were uncommon ( about 1%) of subjects exposed to telithromycin • Telithromycin appeared similar to AMC with elevations in hepatic analytes (specifically, ALT) up to 3 x ULN • More extreme elevations in ALT (> 8 x ULN) were slightly more common among telithromycin treated subjects • A minority of subjects were symptomatic in both treatment arms • There were no cases of liver failure or deaths among hepatic cases • At the 6 month follow-up no subjects were reported with known sequelae, one telithromycin-treated subject had persistent RUQ tenderness on examination x 6 months FDA Anti-Infective AC Meeting